PIP2 domains (also called PIP2 clusters) are a type of cholesterol-independent lipid domain formed from
phosphatidylinositol
Phosphatidylinositol (or Inositol Phospholipid) consists of a family of lipids as illustrated on the right, where red is x, blue is y, and black is z, in the context of independent variation, a class of the phosphatidylglycerides. In such molecul ...
and positively charged proteins in the
plasma membrane. They tend to inhibit
GM1 lipid raft function.
Chemical properties
Phosphatidylinositol 4,5-bisphosphate
Phosphatidylinositol 4,5-bisphosphate or PtdIns(4,5)''P''2, also known simply as PIP2 or PI(4,5)P2, is a minor phospholipid component of cell membranes. PtdIns(4,5)''P''2 is enriched at the plasma membrane where it is a substrate for a number o ...
(PIP2) is a anionic signaling lipid. Its polyunsaturated acyl chains exclude it from GM1 lipid rafts. The multiple negative charges on PIP2 are thought to cluster proteins with positive charges residing in the plasma membrane leading to nanoscale clusters. PIP3 is also clustered away from PIP2 and away from GM1 lipid rafts.
Biological function
PIP2 domains inhibit GM1 domain function by attracting palmitoylated proteins away from GM1 lipid rafts. For this to occur a protein must be both
palmitoylated
Palmitoylation is the covalent attachment of fatty acids, such as palmitic acid, to cysteine (''S''-palmitoylation) and less frequently to serine and threonine (''O''-palmitoylation) residues of proteins, which are typically membrane protein ...
and bind PIP2. Presumably PIP2 could also antagonize PIP3 localization but this has not been shown directly.
PLD2
Phospholipase D2 (PLD2) binds PIP2 and localizes with lipid rafts. Increases in cholesterol overcome PIP2 binding and sequester PLD2 into GM1 lipid rafts away from its substrate
phosphatidylcholine
Phosphatidylcholines (PC) are a class of phospholipids that incorporate choline as a headgroup.
They are a major component of biological membranes and can be easily obtained from a variety of readily available sources, such as egg yolk or soybea ...
. Efflux of cholesterol causes PLD2 to translocate to PIP2 domains where it is activated by
substrate presentation. Both PIP2 signaling and
cholesterol signaling regulate the enzyme.
ACE2 receptor
Angiotensin converting enzyme (ACE2) is regulated by PIP2 localization. The ACE2 enzyme is palmitoylated which drives the protein into GM1 lipids. The enzyme also bind to PIP2 which moves it out of the endocytic pathway. The drug
hydroxychloroquine
Hydroxychloroquine, sold under the brand name Plaquenil among others, is a medication used to prevent and treat malaria in areas where malaria remains sensitive to chloroquine. Other uses include treatment of rheumatoid arthritis, lupus, an ...
blocks ACE2 interaction with PIP2 in multiple cell types shifting its localization.
Other
PIP2 binding proteins
*
PH domain
In chemistry, pH (), historically denoting "potential of hydrogen" (or "power of hydrogen"), is a scale used to specify the acidity or basicity of an aqueous solution. Acidic solutions (solutions with higher concentrations of ions) are ...
PIP2/palmitate proteins
*
GABAA receptor
References
{{Reflist
Lipids